ABCMdb

PMID: 21607646

Venerando A, Pagano MA, Tosoni K, Meggio F, Cassidy D, Stobbart M, Pinna LA, Mehta A
Understanding protein kinase CK2 mis-regulation upon F508del CFTR expression.
Naunyn Schmiedebergs Arch Pharmacol. 2011 May 24., 2011-05-24 [PubMed]

Sentences

No. Mutations Sentence Comment

74 ABCC7 p.Gly551Asp As proof of principle, a new small molecule has recently been reported to re-open the rare mutant G551D CFTR (<5% of alleles) which theoretically cannot transport anions because its nucleotide sandwich is defective in ATP hydrolysis (Accurso et al. 2010). Login to comment 75 ABCC7 p.Gly551Asp In CF, the affected sweat gland duct produces too much sodium and chloride because defective G551D CFTR cannot open its pore to re-absorb chloride which consequently, together with luminal sodium, passes on by the chloride-impermeant apical membrane of the sweat duct onwards to the skin surface. Login to comment 77 ABCC7 p.Gly551Asp That the observed LIMBO reversal is not complete suggests that the pathway from gene to disease is not fully understood and is consistent with this drug`s unexpected effects on CFTR mutants without this G551D-induced ATP hydrolytic defect. Login to comment 79 ABCC7 p.Gly542* This drug is claimed to restore full-length CFTR bearing stop mutations that normally induce nonsense-mediated CFTR decay (for example, the G542X stop mutation in CFTR and others like it that together account for about 10% of CFTR mutants). Login to comment 80 ABCC7 p.Gly542* At the very least, this drug, which was developed to create read-through at single stop codons such as G542X, should reverse the above 'gold standard` sweat test, but it absolutely fails to do so, thus adding further doubt to our ability to fully understand the path from CFTR defect to disease. Login to comment 98 ABCC7 p.Gly551Asp This idea is challenged by a recent study (Comer et al. 2009) examining lung function in CF patients with the above 'severe` G551D CFTR mutant that is supposedly devoid of any channel activity (Briel et al. 1998) in vitro. Login to comment 102 ABCC7 p.Gly551Asp Thus, we have yet another theory-practice paradox of a dead but present G551D CFTR channel that is normally processed to the apical membrane creating better functioning lungs than those with a F508del CFTR missing channel that is degraded in the ER and probably never reaches the apical membrane. Login to comment 103 ABCC7 p.Gly551Asp At the very least, these patient data challenge the widely held notion that G551D is always a 'severe` CF mutation. Login to comment 104 ABCC7 p.Gly551Asp Those proposing the alternative 'knock-in` network dysfunction model would say that after G551D mutation, the sodium channel may not be as hyperactive as found in F508del CFTR, so we might expect better lungs. Login to comment 105 ABCC7 p.Gly551Asp Yet others suggest that G551D CFTR also fails to inhibit the sodium channel in model systems (Briel et al. 1998), and the latest animal data suggest that the very idea of augmented sodium absorption needs to be treated with caution rather than drugs (Chen et al. 2010). Login to comment